Old and novel Interleukin-1 Ligands and Receptors in inflammation and immunity
Istituto Clinico Humanitas, Italy
Humanitas Research Foundation,, University of Milan, Italy
IL-1R like receptors (ILRs), as well as Toll Like Receptors (TLRs), are members of a superfamily of phylogenetically conserved proteins of innate immunity and inflammation, characterized by the presence of a conserved intracellular domain, the Toll/IL-1R (TIR) domain. Most members of both subfamilies are responsible of the activation of an evolutionarily conserved signaling pathway leading to inflammation and innate responses: upon ligand binding, dimerization of receptor TIR domains, recruitment of TIR domain containing adapter proteins and activation of signaling occur. This pathway involves Myeloid differentiation factor 88 (MyD88), IL-1R associated kinases (IRAKs), and tumor necrosis factor receptor-associated factor 6 (TRAF6) and leads to activation of nuclear factor kappa B (NF-kB), activator protein-1 (AP-1), c-Jun N-terminal kinase (JNK), p38 mitogen-associated protein kinase and members of the interferon regulatory factor family.
Depending on the structure of the extracellular region, the family is subdivided in TLRs bearing leucine-rich repeats and ILRs bearing Ig-like domains. Whereas TLRs are receptors for specific pathogen associated molecular patterns and of necrotic cell-derived danger signals and act as sensors for microorganisms and tissue damage, the ILR subfamily includes the receptors and the accessory proteins (AcP) for pro- and anti-inflammatory molecules of the IL-1 family. ILRs are involved in the initiation of an amplification cascade of innate resistance, contribute to the activation and orientation of adaptive immunity and play a key role in inflammatory conditions. In particular, ILRs ligand family includes pro-inflammatory molecules such as IL-1α and IL-1β (IL-1F1), IL-18/IL-1F4, IL-36α/IL-1F6, IL-36β/IL-1F8 and IL-36γ/IL-1F9. Other members of the IL-1 family show anti-inflammatory activity: IL-1Ra/IL-1F3 binds to IL-1R1 inhibiting the recruitment of IL-1RAcP and competes with IL-1α and IL-1β for receptor binding; IL-36Ra binds IL-1Rrp2 antagonizing IL-36α, IL-36β and IL-36γ; IL-37 produces anti-inflammatory effects; and finally IL-33 binds to T1/ST2, recruits IL-1RAcP and induces the expression of anti-inflammatory cytokines.
Uncontrolled or deregulated activation of ILRs- or TLRs-dependent inflammatory and immune responses can be detrimental for the host and potentially causes tissue damage and acute or chronic inflammatory disorders. For the IL-1 system, which has served as a paradigm for the definition of signaling and regulatory mechanisms, the control is exerted at different levels, both extracellularly and intracellularly, for instance by polypeptide antagonists, decoy receptors, signaling molecules and miRNA. In particular, decoy receptors, such as IL-1R2, bind ligands that are no longer available for the transducing receptors or form dominant negative non-signaling complexes with AcPs. TIR8/SIGIRR inhibits the activation of the signaling pathway by TLRs and IL-1R by interfering with the association of adaptor molecules to the receptor complex.
Thus, the family of IL-1 ligands and receptors evolved with the dual role of activating as well as reducing and modulating inflammation and innate and adaptive immune responses. This Research Topic is focused on different members of the IL-1 ligand and receptor family, on their function as activators or suppressors of inflammation, activation and polarization of adaptive responses, on their involvement in pathology and potential therapeutic targeting.